Compounds containing an active methylene group, and process of preparing the same



Patented June 1?, 1947 COMPOUNDS CONTAINING AN ACTIVE I METHYLENE GROUP, AND OF PREPARING THE SAME PROCESS EricT. Stiller, Fanwood, N. J., assignor to Merck & Co.,Inc., Rah'way,- N; J., a corporationo! New Jersey No Drawing. Original application December is, 1

1939, Serial N0. 309,574. Divided and this application December 24, 1942, Serial No. 470,096

8 Claims. (Cl. 260-558) l This invention relates to compounds containing an active methylene group, derivatives of such compounds, and processes of preparing the same. 2

This application is a division otmy copending 5 application Serial No. 309,574 filed December 16, 1939, which has matured into Patent No. 2,306,765, issued Dec. 29, 1942.

I have discovered that the methylene group of acetylacetone, substituted acetylacetone, malonic esters, cyanoacetic esters, etc., will react with compounds which contain a double bond oxygen, or which are capable of forming a double bond oxygen, such as ortho estersand nitrous acid, to introduce an alkoxymethylene or an isonitroso' group into the molecule. The alkoxy methylene group thus introduced may be reacted with ammonia, an amine or an amide having at least one hydrogemto form the corresponding aminomethylene or amidomethylene group. 20.

I have also discovered that the aminomethylene, amidomethylene and isonitroso (the latter in the presence of an agent which can stabilize the amino group, such as an acid anhydride, an acid, etc.) derivatives may be hydrogenated to form the corresponding aminomethyl, amidomethyl, amine salts of acylamino derivatives. These new compounds may be illustrated bythe general formula:

wherein R1 is a member selected from the group consisting of alkoxyacyl, acyl, carbalko and alkoxyalkyl; R2 is selected from the group con... sisting of alkoxy, and hydrogen; R3 is selected The above compounds 'maybe obtained according to the following:

is. 3.0mm

2 m a. R: i=0 3E. &=e

i. o... i. N...

A 1 amide lC oi-ide R1 RI- i i. Jan-cf! in \mcon CHI-0:0

c=N-o11 (mi-i=0 OKs-0:0

HNO:

anhydride v CaH OCHr =0- The compounds of the present invention are from the group consisting of alkoxy, acylamino-' 40 particularly useful asintermediates for the proalkyl and acylamino, and wherein R2 and R1 together may represent a member sele'ctedfrom the group consisting of alkoxymethylene, aminomethylene, acylaminomethylene, alkoxyalkylalkoxymethylene, imino, alkoxyalkylacylaminomethylene, and isonitroso; R4 is a member selected from the group consisting of acyl, alkoxyacyl, alkoxy, and cyanogen.

duction of substituted pyridine and pyridone.

compounds, for example, by. condensing them with a malonic acid derivative such as cyano acetamide, carbamoacetic esters, etc.

The following, examples illustrate methods of carrying out the present invention, but it is to be'understood that theseexamples are given by v way of illustration and not of limitation.

dles.

.Ezcample 1 1 One hundred and forty-four grams of '1- ethoxy-pentane-2A-dione and 148 grams of ethyl orthoformate are mixed with 204 grams of acetic anhydride and'refluxed for 40 minutes. The material distilling up to 140 C. at 15 mm. is re moved, and then the material having a boiling point up to 153 C. at 4 mm. is removed and refractionate'd. 65 grams of 1-ethoxy-3-ethoxymethylenepentane-2,4-dione are. obtained as a pale yellow liquid, 13. P. 145-6 C. at 4 mm. which 5 at8788 C. The yield is 1.65 grams.

on cooling to 0 C. crystallizes as colorless nee- Five grams of 1-ethoxy-3-ethoxymethylenepentane-2,4-dione are dissolved in 20 -cc. of an hydrous ether, cooled in ice,and 4 cc. or alcohol,-

containing 0.43 gm. of dry ammonia added. Im-

mediately crystallization occurs, and after standing at 0 C. over night, the crystals are filtered off and washed with a little cold. ether. From the mother liquors, .a further quantity of the product is obtained. The total yield of, l-ethoxy- 3 aminomethylene pentane 2,4 dione is 3.5 grams. It is purified by recrystallization from ethyl acetate and obtained as colorless needles, melting point 93-94 C. I

1-ethoxy 3 benzoylaminomethylene pentane- 2,4-dione may be obtained by either of two alternative methods. For example, 3 grams of 1-ethoxy-3-ethoxymethylene pentane-2,4 dione and 1.81 grams of benzamide are heated together for 10 minutes at 155 C. The solution darkens considerably. The liquid product after cooling is dissolved in .5 cc. of 80% alcohol and cooled in the refrigerator. 1.8 grams of pale brown needles are obtained, and on dilution of the mother liquors a further 0.6 gram are obtained. 'The' 1-ethoxy-3-benzoylaminomethylene pentane-2,4- dione is purified by crystallization from dilute alcohol and obtained as pale yellow needles,-M. P.- 95-96" C.

Alternatively, 2.3 grams of l-ethoxy-3-aminomethylenepentane-2,4-dione are dissolved in 1.1 cc. dry pyridine and cooled to 0 C. 1.95 cc. benzoyl chloride are added drop-wise and the mixture allowed to stand for 3 hours at roomtemperature. Water is added,, the mixture extracted with ether, the ether is thoroughly washed with water, and dried over sodium sulfate. The

"product obtained on removal of the ether is disa viscous pale brown oil, which upon crystallization from ether and recrystallization from ethyl acetate, gives colorless fine needles, melting point 89-90? C. Yield 1.65 grams.

Example 2 2.2 grams V of 3-benzoylaminomethylene pentane-2,4-dione are dissolved in 100 cc. ethyl alcohol and hydrogenated in the presence of 0.1 gram -'of a platinum catalyst. The theoretical amount of hydrogen is taken up rapidly. After removal v is 8 grams.

Example 3 2 grams of ethyl-a-benzoylaminomethyleneacetoacetate are dissolvedln 150 .cc. of ethyl alcohol and hydrogenated in the presence of 0.1 gram of a platinum catalyst. The catalyst is removed by filtration and the solventremoved by evaporation under reduced pressure.- The ethyl-amenzoylaminomethyl acetoacetate is a faintly yellow oil whichcrystallizes on standing. After recrystallization from ether-petroleum ether, it'is obtained as colorless needles, melting point 56 C. Yield 1.90 grams.

I Example 4 26 grams of ethyl-gamma-ethoxy acetoacetatc, 22.1 grams of ethyl orthoformate, and 30.5 grams of acetic anhydride are refluxed for 40 minutes. The reaction mixture is then distilled until the temperature reaches 122 C. The residue is distilled through a fractionating column at 8 mm. up to 165 C. and then refractionated at 5 mm. The fraction boiling at l46 -52 C. at 5 mm. crystallizes on standing at 0 C. After separating from a little oily material and recrystallizing from petroleum ether, the ethyl-rr-ethoxyrnethylenegamma-ethoxy acetoacetate is obtained as colorless fine long needles, melting point 57-58 C. The'oily material on cooling gives further crystals. Total yield 19.7 grams.

12.8 grams of ethyl-a-ethoxymethylene-gamma-ethoxy acetoacetate are mixed with 6.73 grams benzamide, and the mixture heated at 150 C. for 50 minutes. After cooling, alcohol is added and the product is obtained as pale brown plates on standing 'at 0 C. The yield of ethyl-a-benzoylaminomethylene-gamma ethoxy acetoacetate On recrystallization from alcohol it melts at 96-98 C. 4

2 grams of ethyl-a-benzoylaminomethylenegamma-ethoxy acetoacetate are dissolved in 150 cc. alcohol and hydrogenated in the presence of 0.1 gram of a platinum catalyst. The catalyst is removed by filtration and the solvent removed by concentration under reduced pressure. ethyl a benzoylaminoinethyl gamma ethoxy acetoacetate obtained is distilled and obtained as an almost colorless oil.

Example 5 156 grams methoxy-acetonitrile are mixed with 128.6 cc. of absolute ethyl alcohol and 100 cc. absolute ether. Dry hydrogen chloride (88 grams) are passed into the mixture which is kept cool imino -ethyl-ether hydrochloride are suspended in 2300 cc.. of absolute alcohol and shaken at room temperature for two weeks. The solids are then removed by filtration and the mother liquor allowed to stand in contact with 10 grams of freshly ignited potassium carbonate over night to remove traces of acid. The filtrate from the potassium carbonate is fractionated at 15 mm. of the catalyst by filtration, the filtrate is conpressure; the first fraction boiling up to 35 C.

The

consists mainly of alcohol, the second fraction j p to 70 C. consists mainlyofethylmethoxy-acetate.' The fraction boiling at 70- 75 C. is the crude methoxy-ethyl-ortho-acetate. This fraction is kept at C. for 16 hours, and the small amount of methoxy-acetamid which crystallizes out is filtered off. The filtrate is re- 1 fractionated at ordinary pressure and the fracacetate, 65 grams acetoacetic ester, and 62 grams of freshly distilled acetic anhydride .is refluxed for 4 hours. The ethyl acetate and acetic acid asaasca removed in vacuum,

and'the 3-(acetylamino)- acetylacetone crystallizes in colorless prisms: yield 2.2 grams. lifter recrystallization from ethyl acetate, it has a melting point of 93-94 v(I.

I Example 8' '15 grams of ethoxy-acetylacetone are, stirred wlth500 cc. of 7% sulfuric acid cooled in ice, a

solution of 35 grams of sodium nitrite in 150 cc.

of water is slowly dropped in, and the mixture allowed to stand at 0 C. for one-half hour. The

formed during the reaction are distilled ofl until the temperature of the liquid in the flask reaches 120 C. The mixture is again refluxed for one hour, and then the ethyl acetate and,

acetic acid are distilled oil as before. The residue is then fractionated at 10 mm. pressure and the material boilingto 78 C. removed. The pressure is then reduced to 5 mm. and the fraction boiling up to 105 C. is refractionated at one mm.

' pressure. 7.5 grams of a colorless, mobile oil are obtained which is l-methoxy-Z-ethoxy-3carbethoxy-2-pentene-4-one. v

Example 6 A mixture of 113 grams cyanacetic ester, 192 grams ethyl-methoxy-ortho-acetate and 204: grams acetic anhydride are refluxed for one hour,

' and the pale yellow mixture is then distilled up to 115 C. The residue is again refluxed foran hour'and again distilled till the vapour tempera ture reaches 115' C. The residue is distilled at 15 mm. till the vapour temperature reaches 106 C. The residue gives as a main fraction a very faintly yellow liquid, boiling point 129-130 C. at 0.6 mm. Yield 70 grams. On cooling at 0 C., the product crystallizes and on recrystallization from ether-petroleum ether, ethyl a-cyano-fl-ethoxygamma-methoxy crotonate is obtained as colorless square plates, melting point -i2-44 C. Upon treating the latter compound .with benzamide, ethyl c: -cyano-i8-benzoy1amino-gamma-methoxy crotonate is obtained.

Example 7 grams of acetylacetone are mixed with 500 cc. of 7% sulfuric acid, and the mixture is cooled to 0 C. 35 grams of sodium nitrite dissolved in 150 cc. H2O are slowly dropped in with stirring. After the addition is complete, the mixture is stirred for an additional 15 minutes and then extracted with ether. The ether is dried with sodium sulfate after washing with water. The ether is removed and the syrupy residue crystallizes on scratching. The isonitroso-acetylacetone" is dried and freed from nitrous fumesin vacuum. Melting Point 75 C.

2.15 grams of isonitroso-acetylacetone are dissolved in 50 cc. of freshly distilled acetic anhydride, and hydrogenated in the presence of Adam's platinum catalyst at ordinary pressure. The theoretical amount of hydrogen (800 cc.) is taken up in 20 minutes, and the reaction is solution is extracted flvetimes with ether, the

extract dried with sodium sulfate, and the ether removed in vacuum. The syrupy residue is dried in vacuum overnight over potassium hydroxide; 7

Yield, 88 grams. Partial crystallization takes place. It is taken up in the minimum amount of ether, and petroleum ether is carefully added to the cooled solution until turbity appears. Upon vigorous scratching and cooling to -10 63., isonitroso-ethoxy-acetylacetone crystallizes in colorless thin plates. Itis filtered, and washed with petroleumzether-ether (30:70). Yield, 18 grams. 4

After recrystallization from ether-petroleum ether, the thin colorless plates point of 93-95 C. g t

- The mother liquor on evaporation gives a syrup which crystallizes on standing, and on treatment with ether-petroleum ether, gives a further 8 grams of crystalline material.

The above mother liquor on evaporation again crystallizes, and after filtering from syrupy material, gives a further 25 grams of isonitroscethoxy-acetylacetone.

By repeating these procedures, further pure material can be obtained.

10 grams of isonitroso-ethoxy-acetylacetone are dissolved in 225 cc. of freshly distilled acetic anhydride, and hydrogenated at ordinary pres sure in the presence of 0.3 gram of platinum oxv ide catalyst. The theoretical amount of hydrogen is taken up rapidly, and the hydrogenation isstopped. After removal of the catalyst, the acetic anhydride is removed in vacuum at a low temperature. The" residue (12 grams) is a p yellow oil. I All attempts to crystallize this material fail, although a small amount of crystalline by-product is obtained (0.3 gram, M. P. 101- 102 C.) from ether-petroleum ether, which anlyzes for CnHuOaN. The syrupy 3-(acetylamino) -ethoxy-acetylacetone can not be distilled at 0.3 mm. without extensive decomposi- Modifications may be made in carrying out the present invention without departing from the spirit and scope'thereof, and I am to be limited only by the appended claims.

=CHN

wherein R1 and R2 are substituents selected from the class consisting of alkyl and alkoxyalkyl groups and R: is a substituent selected from the stopped. The catalyst is filtered off, the solvent class consisting of hydrogen and acyl groups,

have a melting to produce a. substance represented by the .for-

mula:

to H H-CHI-N l wherein R1 and R2 are substituents selected from the class consisting of i alkyl and alkoxyalkyl groups; and R3 is a. substituent selected from the class consisting of hydrogen and acyl groups. I

2. A composition of matter represented by the formula: 9

wherein R1 and R: are substituents selected from produce 3 a. 1-ethoxy-2:4-diketo-3-acylaminomethyl pentane, I

5. The process that comprises catalytically hydrogenatiug the; oleflnic bond in a 2 :4-diketothe class consisting of alkyl, and alkoxyalkyl groups; and R: is a substituent selected from the class consisting of hydrogen and acyl groups.

3. The process that comprises catalytically hydrogenating the oleflnicbond in a 2:4-diketo- '3-aminomethylene pentane to produce e. 2:4-

diketo-3-aminomethy1-pentane.

4. The process that comprises catalytically hydrogenating the olefinic bond in a 'l-ethoxy- 2z iediketo-3-acylaminomethylene pentane to S-acylamin'omethylene pentaneto produce a. 2:4- diketQ-8-acylaminomethyl pentane.

6. 1-ethoxy-2:4-diketo-3-aminomethyl tane.

7. l-ethoxy-md-diketo 3 acylaminomethyl pentane. i

v 3. 2:4-diketo-3-aminomethyl pentane.

v ERIC T. STILLER.

- REFERENCES CITED The following references are of record in the fileo! this patent:

UNITED STATES PATENTS pen- OTHER REFERENCES Claissen Annalen der Chem. (Liebig) vol. 297, pp. 1 to 21, 29 to 33, 57 to 69. (Copies in the Patent Ofilce Scientific Library.) 

